Alzheimer's disease (AD) progresses over many years from a preclinical stage to mild cognitive impairment (MCI) to dementia. The notion of preclinical AD has emerged from rigorous clinical and pathological correlations conducted in several longitudinal studies, including ours on the Baltimore Longitudinal Study of Aging (BLSA). Neuropathologically, preclinical AD can be generally defined by the presence of substantial neuritic plaques and neurofibrillary/tau changes in subjects with documented normal cognition. In this project, we propose studies to achieve a more rigorous definition of preclinical AD in terms of structural and biochemical parameters. Specifically, we will measure changes in the number of neurons and synaptic markers in specific regions of the hippocampus and entorhinal cortex (ERG) of individuals from the BLSA and Clinic cohorts, including controls, preclinical AD, and MCI. We will also examine how Abeta and neurofibrillary/tau changes interact and contribute to neuronal and synaptic degeneration in the hippocampus and entorhinal cortex in preclinical AD. Specifically, we will focus on the dendritic field of CA1 pyramidal neurons and on the projections of layer II ERC neurons via the perforant pathway onto the molecular layer of granule cells. A thorough understanding of the preclinical stage of AD and the early mechanism of neurodegeneration is critical since this stage represents and ideal temporal window for the use of emerging preventive and therapeutic strategies in AD.